Association of Ki-ras with amplified DNA sequences, detected in human ovarian carcinomas by a modified in-gel renaturation assay.

A modified in-gel DNA renaturation technique, which detects DNA sequences amplified greater than 7-fold in human DNA, was used to analyze gene amplification in surgical specimens of primary and metastatic ovarian carcinomas. Amplified DNA sequences were detected in two of eight tumors. Hybridization of these samples with different oncogene probes revealed that both tumors contained an amplified Ki-ras gene, which in one case was coamplified with c-myc. In one of the tumors, Ki-ras was found to be amplified in both the primary tumor and three different metastatic nodules. No mutations at codons 12 or 61 of Ki-ras were detected in these tumors. No additional cases of Ki-ras or c-myc amplification were detected by Southern hybridization in the tumors that were found to be amplification negative by modified in-gel renaturation assays. These results indicate that gene amplification in ovarian carcinomas is likely to involve the Ki-ras oncogene.

The role of surgical debulking in cancer of the uterine cervix.

From 1978 to 1985, 159 women with advanced cervical cancer received definitive radiation therapy following extraperitoneal surgical staging including pelvic lymph node dissection and periaortic lymph node sampling. Relapse-free survival was a strong function of peritoneal and nodal metastases but was independent of clinical stage. The 5-year relapse-free rate fell from 86% in women without pelvic node metastases to 0% in those with unresectable pelvic node metastases. Women with microscopically positive pelvic node metastases had virtually the same (56%) relapse-free rate as those with grossly positive but completely resected metastases (57%). The overall pelvic failure rate was 16.4% and was significantly higher in women with unresectable pelvic node metastases. Periaortic and peritoneal metastases substantially increased the probability of recurrence. Although histologic grade was prognostically significant, histopathologic category was not. Severe enteric morbidity occurred in 3.6% of patients treated solely to the pelvis and in 7.9% of patients treated to the pelvis and periaortics. Therapeutic implications of debulking pelvic node metastases are discussed.

Radical vulvectomy with postoperative irradiation for vulvar cancer: therapeutic implications of a central block.

PURPOSE/OBJECTIVE: To report the long-term results of vulvectomy, node dissection, and postoperative nodal irradiation using a midline vulvar block in patients with node positive vulvar cancer. METHODS AND MATERIALS: From 1971 through 1992, 27 patients with carcinoma of the vulva and histologically involved inguinal lymph nodes were treated postoperatively with radiation therapy after radical vulvectomy and bilateral lymphadenectomy (n = 25), radical vulvectomy and unilateral lymphadenectomy (n = 1), or hemivulvectomy and bilateral lymphadenectomy (n = 1). Federation Internationale de Gynecologic et d'Obstetrique stages were III (n = 14), IVA (n = 8), and IVB (n = 5) squamous cell carcinoma. Inguinal lymph nodes were involved with tumor in all patients (average number positive = 4, range 1-15). Postoperative irradiation was directed at the bilateral groin and pelvic nodes (n = 19), unilateral groin and pelvic nodes (n = 6), or unilateral groin only (n = 1). These 26 patients had the midline blocked. In addition, one patient received irradiation to the entire pelvis and perineum. Doses ranged from 10.8 to 50.7 Gy (median 45.5) with all patients except 1 receiving > or = 42.0 Gy. RESULTS: Actuarial 5-year overall survival and disease-free survival estimates were 40% and 35%, respectively. Recurrences developed in 63% (17/27) of the patients at a median of 9 months from surgery (range 3 months to 6 years) and 15 of these have died; two patients with recurrences are surviving at 24 and 96 months after further surgery and radiation therapy. Central recurrences (under the midline block) were present in 13 of these 17 patients (76%), either as central only (n = 8), central and regional (n = 4), or central and distant (n = 1). Additionally, three patients developed regional recurrences and one patient developed a concurrent regional and distant relapse. One patient developed a squamous cell cancer of the anus under the midline block 54 months after the initial vulvar cancer and an additional patient developed transitional cell carcinoma of the ureter (outside the radiation field) 12 months after diagnosis. Factors associated with a decreased relapse-free survival included increasing Federation Internationale de Gynecologic et d'Obstetrique stage (p = 0.01) and invasion of the tumor into the subcutaneous (SC) fat or deep soft tissue (p = 0.05). Chronic lower extremity edema developed in four patients, but there have been no other complications. CONCLUSIONS: Radical vulvectomy has often been considered sufficient central treatment for vulvar carcinoma, with postoperative irradiation directed only to the nodes. Although designed to protect the radiosensitive vulva, use of a midline block in this series resulted in a 48% (13/27) central recurrence rate, much higher than the 8.5% rate previously reported with this technique. Routine use of the midline block should be abandoned and, instead, postoperative irradiation volumes should be tailored to the individual patient.

The Brenner tumor: a clinicopathologic review.

The Brenner tumor of the ovary has been the topic of voluminous clinical and pathologic literature since its original description by Macnaughton-Jones in 1898. One of the major problems confronting most investigators of this uncommon neoplasm has been the question of histogenesis. There is general agreement that the tumor is derived from surface (coelomic) epithelium, as are the serous and mucinous cystadenomas. Most Brenner tumors are asymptomatic except for some which have features suggestive of estrogen production. The major pathologic variants are the proliferating and the malignant Brenner tumors; a poor prognosis is associated with the latter neoplasm. Approximately 30% of all benign Brenner tumors have a second histologic type of tumor in the ipsilateral or contralateral ovary, a serous or mucinous cystadenoma in most cases. Brenner tumors have also been reported in the broad ligament and in the testis on rare occasions.

Paraaortic lymph node radiotherapy in cancer of the uterine corpus.

From 1973 through 1982, 48 women received 4500 to 5075 rads to the paraaortic lymph nodes as part of their primary management for cancer of the uterine corpus. One patient developed severe enteric morbidity. Five-year survival rates were 52% in the total group, 57% in clinically staged patients, and 47% in surgically staged patients. Patients with surgically confirmed pelvic lymphatic spread had a five-year survival rate of 67%. Patients with surgically confirmed paraaortic spread alone or pelvic and paraaortic spread had five-year survival rates of 47 and 43%, respectively. Eighty-eight percent of recurrences were outside of the radiation portals. In contradistinction to much of the last decade's literature, radiation therapy has salvaged a substantial fraction of patients with nodal metastases, and morbidity rates have been acceptable.

Pelvic coccidioidomycosis.

Pelvic inflammatory disease due to Coccidioides immitis is rare. However, female patients with disseminated coccidioidomycosis may have unrecognized pelvic involvement as pelvic examinations are frequently not performed. Inappropriate and inadequate therapy of pelvic coccidioidomycosis may very well contribute to the demise of such patients. The diagnosis must also be suspected in patients with pelvic abscesses which do not respond to antibiotic therapy and conventional surgery. Extirpative surgery, in addition to amphotericin B, is frequently necessary to eradicate the disease. A patient is reported whose course illustrates these conclusions.

Fibromatosis of the female pelvis.

Fibromatosis is a benign, infiltrating, nonmetastasizing neoplasm which is rarely completely resected. Therefore, the incidence of recurrence is high. Fibromatosis is more common in females and is frequently diagnosed during pregnancy. Inasmuch as fibromatosis of the female pelvis appears to be a discrete entity, management poses significant problems for the gynecologist. Radiation therapy, frequently used following incomplete resection or for recurrence, is undesirable due to the loss of ovarian function and fertility. Hormonal manipulation and combination chemotherapy are alternatives which have been effective in some reports. Three patients with pelvic fibromatosis, referred within 1 year, are reported. The various aspects of this neoplasm and the diagnostic procedures are discussed. Treatment modalities whose effects are reversible are recommended for recurrent fibromatosis. Radiation therapy can be reserved for patients in the older age groups or for those with progressive disease not responding to other therapy.

Prediction of malignancy using transvaginal color flow Doppler in patients with gynecologic tumors.

Eighty-five patients referred to the Women's Cancer Center, University of Minnesota had transvaginal color flow Doppler performed to determine if pelvic malignancy could be predicted by blood flow assessment. Their mean age was 49 years (range 21-86 years). Thirty-five patients were subsequently found to have malignant tumors of the cervix, uterus or ovary. The presence of increased intratumoral blood flow as depicted by color flow Doppler had a sensitivity of 83%, specificity of 100%, positive predictive value (PPV) of 100% and negative predictive value (NPV) of 89% for malignancy. The mean intratumoral Pulsatility Index (PI) of the patients with malignant tumors was 0.81 (SD 0.24; range 0.3-1.2), which was significantly lower than for the benign group (P = 0.001). A PI of

Phase II trial of piperazinedione (NCS 135758) in the treatment of advanced or recurrent squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study.

Thirty-eight patients with advanced or recurrent squamous cell carcinoma of the cervix no longer amenable to management with surgery and/or radiotherapy were given piperazinedione 9 mg/m2 intravenously every 3 weeks. Five (13%) experienced either complete or partial regression of disease, while 13 (34%) demonstrated stable disease. Responses were relatively short (median 3 months) with responders surviving significantly longer than nonresponders (median 20.3 months vs. 3.0 months, p = 0.01). Adverse effects consisted primarily of myelosuppression (61%) and nausea and vomiting (47%) and generally were mild to moderate and tolerable. The drug has minimal activity and tolerable adverse effects and could be considered for trials of combination chemotherapy in this disease.

The impact of extraperitoneal surgical staging on morbidity and tumor recurrence following radiotherapy for cervical carcinoma.

From 1971 through 1981, 83 nonsurgically staged women with cervical cancer received extended-field radiotherapy on the basis of abnormal lymphangiogram, obstruction on intravenous pyelogram, or extensive pelvic tumor volume. From 1978 through 1981, 61 surgically staged patients underwent radiation therapy; of these, the 21 with positive lymph nodes received periaortic radiation. No increase in morbidity was found in these patients. Survival, relapse rate, and sites of treatment failures were similar in the positive lymphangiogram group and in the surgically staged patients with positive nodes.

The integration of whole abdominal radiotherapy and intraperitoneal cisplatin into the primary management of advanced ovarian carcinoma.

Eleven women with Stages III and IV epithelial ovarian carcinomas were entered into a protocol consisting of concurrent whole abdominal radiotherapy and intraperitoneal cisplatin followed by additional intraperitoneal cisplatin. The entire abdomen received 20 Gy in 20 fractions with no renal or hepatic shielding. Intraperitoneal cisplatin dosage was 20 mg/m2 weekly during radiation and 90 mg/m2 monthly thereafter for an additional three courses. Patients with Stages IIIC and IV had a median survival of 18 months and a two-year actuarial survival of 32%. Primary failure sites were the abdomen, pleura, and lymph nodes. Acute toxicity during radiotherapy was comparable to patients treated with radiation alone. No chronic renal, hepatic, or enteric complications were observed. Although the protocol did not have substantial efficacy in advanced disease, its toxicity was moderate enough to consider its use in less advanced cancers with peritoneal metastases. In particular, the protocol can be considered for women with ovarian cancer with no gross residuum and for women with papillary serous carcinoma of the uterine corpus.

Effect of cis-platinum on tolerance to radiation therapy in advanced cervical cancer.

Women with advanced carcinoma of the uterine cervix are at high risk for the development of local, regional, and distant metastases. Thus, both effective systemic agents and radiosensitizers could be useful adjuvants. However, because a substantial fraction of women with advanced cervical neoplasms are cured with radiation therapy, such experimental agents must not compromise the administration of conventional therapy. Cis-platinum is particularly appealing as it has both radiosensitizing properties and activity in metastatic cervical cancer. The present study examined the effect of weekly cis-platinum on radiation tolerance in 29 women with advanced cervical cancers. Although toxicity was acceptable, no marked enhancement in survival could be demonstrated.

Multimodality therapy for advanced and recurrent vulvar squamous cell carcinoma. A pilot project.

From 1985 to 1989 eight women with advanced or recurrent vulvar carcinoma were treated at the Women's Cancer Center of the University of Minnesota Hospital and Clinic. Each received a combination of 5-fluorouracil, mitomycin C and cisplatin during radiotherapy. Five of the eight women who underwent posttreatment radical vulvectomy had acceptable operative morbidity. Six patients experienced a complete clinical response. Of them, one had microscopic residual disease in the surgical specimen. One patient with recurrent vulvar carcinoma experienced progression of disease on therapy. One death was attributable to chemotherapy toxicity, and two patients died of intercurrent disease. The overall survival rate at 27 months was 33%. This multimodality approach to the treatment of advanced vulvar carcinoma should be considered when designing a therapeutic approach to treating extensive or resistant vulvar carcinoma.

Choriocarcinoma presenting as a complication of elective first trimester abortion.

PIP: A case of metastatic gestational trophoblastic disease detected at a routine 2-week post-abortion examination is presented. The subject was an 18-year old unmarried white gravida 1, para 0 female. At the post-abortion examination, a right adnexal mass was fixed in the pelvis. The pregnancy test still yielded a positive result. Laparotomy was performed and revealed a malignant trophoblast on the serosal surface on the uterus at the site of a spontaneous perforation. Histologic examination of the original endometrial contents revealed a hydatiform mole with 1 area of myometrial invasion. The patient was put on triple chemotherapy and antibiotic therapy. She has since been asymptomatic and is currently taking oral contraceptive medication. The incidence of molar pregnancy is 1/1200 to 2000 pregnancies in the U.S. That of choriocarcinoma is even more rare. Choriocarcinoma follows as a malignant sequelae in nearly 3% of patients with hydatiform mole. It used to be the most uniformly and rapidly fatal malignancy in women. It is currently the one solid malignancy that can be cured with chemotherapy, and normal subsequent pregnancies have even been reported. All tissues removed during an elective abortion must be carefully examined. Pathologists must describe microscopic findings of tissue and not submit reports with gross diagnoses such as 'products of conception'. Villi of normal pregnancy must be identified if accurate diagnoses are to be made and tragedies avoided.^ieng